JPH10158212A - Production of 2-phenylbutylic acid derivatives - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain, in good yield and short time, the subject compound which is important as a medical intermediate, in a single process using an inexpensive reaction reagent by hydrolyzing phenylbutyronitrile compound using sulfuric acid. SOLUTION: The objective compound expressed by formula II (e.g.; 2- phenylbutylic acid) is obtained by carrying out hydrolysis of 2-phenylbutyronitrile compound (e.g.; 2-phenylbutyronitrile, etc.) expressed by formula I (R is H, an alkyl, a halogen) in the presence of sulfuric acid having concentration of 55-75wt.%. at 90 deg.C or higher. The preferred amount of sulfuric acid used in the reaction is two or more molar times of the prescribed nitrile compounds. The reaction is carried out free from solvent. The objective compound is capably obtained by a process, for example, mixing 2-phenylbutyronitrile and sulfuric acid, after the reaction the obtained reaction mixture is extracted by using a hydrophobic organic solvent, concentrating the obtained organic layer under reduced pressure.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for producing a 2-phenylbutyric acid compound.

[0002]

2. Description of the Related Art A 2-phenylbutyric acid compound is an important compound as a pharmaceutical intermediate. Conventionally, as a method for producing a 2-phenylbutyric acid compound, for example, a method of reacting phenylacetic acid and sodium hydride and then reacting with ethyl bromide (Org.Synth.VI.p.517 (1972)), And sodium amide, followed by reaction with carbon dioxide (Org.Synth.VI.p.84
5 (1972)], a method of reacting n-butyrophenone and pyrrolidine to obtain enamine, then reacting the obtained enamine with diphenylphosphoric azide to obtain amidine, and then hydrolyzing the obtained amidine [Chem. Pharm.Bul
l, 21, 564 (1983)], but all of these methods require a plurality of steps and have high activity.
It was necessary to use reagents that were not easy to handle.

As a method for obtaining 2-phenylbutyric acid from 2-phenylbutyronitrile in a single step, hydrolysis using an enzyme [Tetrahedron Asymmetry, 1543 (1992), Te
trahedron Asymmetry, 1085 (1993)) is known,
This method has a problem that the yield is low and the reaction time is long.

[0004]

Accordingly, the present inventors have conducted intensive studies to develop a method capable of producing a 2-phenylbutyric acid compound in a short time with good yield using a low-cost reaction reagent in a single step. By performing hydrolysis in a specific temperature range using sulfuric acid at a specific concentration, 2-
The present inventors have found that a phenylbutyric acid compound can be produced, and have reached the present invention.

[0005]

That is, the present invention provides a compound represented by the following general formula (1): (Wherein, R represents a hydrogen atom, an alkyl group or a halogen atom). Hydrolyzing a 2-phenylbutyronitrile compound represented by the formula below at 90 ° C. or higher using sulfuric acid having a concentration of 55 to 75% by weight. General formula (2) (Wherein, R has the same meaning as described above).
It is intended to provide a method for producing a phenylbutyric acid compound.

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION The alkyl group represented by the substituent R in the 2-phenylbutyronitrile compound represented by the general formula (1) is methyl, ethyl, n-propyl, isopropyl, n-butyl. And a t-butyl group, and a halogen atom is exemplified by a fluorine atom, a chlorine atom and a bromine atom.

The 2-phenylbutyronitrile compound includes, for example, 2-phenylbutyronitrile, 2-phenylbutyronitrile,
(3-methylphenyl) butyronitrile, 2- (4-methylphenyl) butyronitrile, 2- (3-ethylphenyl) butyronitrile, 2- (4-ethylphenyl) butyronitrile, 2- (3-n-propylphenyl) butyronitrile, 2- (4-n-propylphenyl) butyronitrile, 2- (3-isopropylphenyl) butyronitrile, 2- (4-isopropylphenyl) butyronitrile, 2- (3-n-butylphenyl) butyronitrile, 2- (4-n -Butylphenyl) butyronitrile,
2- (3-t-butylphenyl) butyronitrile, 2-
(4-t-butylphenyl) butyronitrile, 2- (3
-Fluorophenyl) butyronitrile, 2- (4-fluorophenyl) butyronitrile, 2- (3-chlorophenyl) butyronitrile, 2- (4-chlorophenyl) butyronitrile, 2- (3-bromophenyl) butyronitrile, 2- (4 -Bromophenyl) butyronitrile and the like.

The concentration of sulfuric acid used in the present invention is 55 to 7
It must be 5% by weight. If the concentration of sulfuric acid is less than 55% by weight, the yield is low, and if it exceeds 75% by weight, the obtained 2-phenylbutyric acid tends to be colored and the yield tends to be low. The amount of the sulfuric acid to be used is usually at least 2 mol times, preferably at least 3 mol times, relative to 2-phenylbutyronitrile. The reaction is usually carried out without using a solvent, and the reaction temperature is 90 ° C. or higher, preferably 90 ° C. or higher and the boiling point of the reaction system or lower.

At the time of the reaction, for example, 2-phenylbutyronitrile and sulfuric acid may be mixed, and after the mixing, the temperature may be raised to the reaction temperature to carry out the reaction. After the reaction, the obtained reaction mixture is extracted using a hydrophobic organic solvent such as toluene, and the like, and the obtained organic layer is concentrated under reduced pressure to obtain the desired 2-phenylbutyric acid compound. When the 2-phenylbutyric acid compound is precipitated in the reaction mixture after the reaction, the precipitated 2-phenylbutyric acid compound may be collected by filtration, but may be added to an alkaline aqueous solution such as an aqueous sodium hydroxide solution. PH of the mixture
Is adjusted to 0 or more, followed by extraction, and the obtained organic layer is concentrated under reduced pressure, whereby a 2-phenylbutyric acid compound can be easily obtained.

The 2-phenylbutyric acid compound thus obtained includes, for example, 2-phenylbutyric acid, 2- (3-methylphenyl) butyric acid, 2- (4-methylphenyl) butyric acid,
-(3-ethylphenyl) butyric acid, 2- (4-ethylphenyl) butyric acid, 2- (3-n-propylphenyl) butyric acid,
2- (4-n-propylphenyl) butyric acid, 2- (3-isopropylphenyl) butyric acid, 2- (4-isopropylphenyl) butyric acid, 2- (3-n-butylphenyl) butyric acid,
2- (4-n-butylphenyl) butyric acid, 2- (3-t-
Butylphenyl) butyric acid, 2- (4-t-butylphenyl) butyric acid, 2- (3-fluorophenyl) butyric acid, 2-
(4-fluorophenyl) butyric acid, 2- (3-chlorophenyl) butyric acid, 2- (4-chlorophenyl) butyric acid, 2-
(3-bromophenyl) butyric acid, 2- (4-bromophenyl) butyric acid and the like can be mentioned.

[0011]

According to the method of the present invention, 2-phenylbutyric acid can be produced in good yield in a short time.

[0012]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples.

Example 1 2-phenylbutyronitrile (16.4 g) was added dropwise over 30 minutes to 60% by weight sulfuric acid (73.7 g) heated to 60 ° C. Thereafter, the temperature was raised to 100 ° C., and the mixture was stirred at the same temperature for 43 hours. Thereafter, extraction with 20 ml of toluene was performed twice, the obtained organic layers were combined, concentrated under reduced pressure, and the obtained residue was dried to obtain crystals of 2-phenylbutyric acid (colorless, 20.9 g, 2-phenylbutyric acid). (Butyric acid content: 88.3% by weight) was obtained (yield: 99.7%).

Example 2 2-Phenylbutyronitrile (16.4 g) was added dropwise to 60% by weight sulfuric acid (73.7 g) heated to 60 ° C. over 30 minutes. Thereafter, the mixture was stirred for 4 hours while heating and refluxing (temperature: 139 ° C.). Then, 20 ml of toluene
The obtained organic layers were combined, concentrated under reduced pressure, and the obtained residue was dried to give 2-phenylbutyric acid crystals (colorless, 18.3 g, 2-phenylbutyric acid content 96). 0.3% by weight) (yield 95.2%).

Example 3 2-Phenylbutyronitrile (16.4 g) was added dropwise to 60% by weight sulfuric acid (73.7 g) heated to 60 ° C. over 30 minutes. Thereafter, the mixture was stirred for 6 hours while heating under reflux (temperature: 133 ° C.). Then, 20 ml of toluene
The obtained organic layers were combined, concentrated under reduced pressure, and the resulting residue was dried to give crystals of 2-phenylbutyric acid (colorless, 18.2 g, 2-phenylbutyric acid content 96). % By weight) (yield 94.1%).

Example 4 2-Phenylbutyronitrile (16.4 g) was added dropwise over 30 minutes to 70% by weight sulfuric acid (63.1 g) heated to 60 ° C. Thereafter, the temperature was raised to 100 ° C., and the mixture was stirred at the same temperature for 23 hours. Thereafter, the pH was adjusted to 1 by adding a 5% by weight aqueous sodium hydroxide solution, and then extraction was performed twice using 20 ml of toluene. The obtained organic layers were combined, concentrated under reduced pressure, and the obtained residue was dried. hand,
Crystals of 2-phenylbutyric acid (colorless, 18.2 g, 2-phenylbutyric acid content 99.1% by weight) were obtained (yield 97.4%).
%).

COMPARATIVE EXAMPLE 1 2-Phenylbutyronitrile (16.4 g) was added dropwise to 50% by weight sulfuric acid (88.4 g) heated to 60 ° C. over 30 minutes. Thereafter, the temperature was raised to 100 ° C., and the mixture was stirred at the same temperature for 43 hours. Then, 20 ml of toluene
The obtained organic layers were combined, concentrated under reduced pressure, and the obtained residue was dried to give crystals of 2-phenylbutyric acid (colorless, 21.1 g, 2-phenylbutyric acid content 56%). 0.6% by weight) (yield 64.5%).

Comparative Example 2 2-Phenylbutyronitrile (16.4 g) was added dropwise over 30 minutes to 98% by weight sulfuric acid (45.2 g) heated to 60 ° C. Thereafter, the temperature was raised to 100 ° C., and the mixture was stirred at the same temperature for 8 hours. Thereafter, extraction with 20 ml of toluene was performed twice, and the obtained organic layers were combined, concentrated under reduced pressure, and the obtained residue was dried to obtain crystals (yellow, 1).
9.7 g). When the crystals were analyzed by gas chromatography, 2-phenylbutyric acid could not be detected.

Claims (2)

[Claims] 1. The general formula (1) (Wherein, R represents a hydrogen atom, an alkyl group or a halogen atom). Hydrolyzing a 2-phenylbutyronitrile compound represented by the formula below at 90 ° C. or higher using sulfuric acid having a concentration of 55 to 75% by weight. General formula (2) (Wherein, R has the same meaning as described above).
A method for producing a phenylbutyric acid compound. 2. The method for producing a 2-phenylbutyric acid compound according to claim 1, wherein the amount of the sulfuric acid used is 2 mol times or more of the 2-phenylbutyronitrile compound.